Since the development of the first nonsteroidal antiinflammatory agents (NSAIDs) in the early 1960's, much work has been done to elucidate the mode of action of these compounds in vivo. It is currently believed that these materials exert their therapeutic effects by inhibiting the action of the cyclooxygenase enzyme on arachidonic acid, thus blocking the formation of the prostaglandins (PG's), potent mediators of inflammation.
More recently it has been discovered that the enzyme 5-lipoxygenase catalyzes the first two steps in the formation of a series of biologically important metabolites of arachidonic acid, the leukotrienes. These metabolites were found to be potent regulators of vascular permeability, one of the classic signs of inflammation. In addition, leukotriene B.sub.4 (LTB.sub.4) has been shown to be a powerful chemotaxin for phagocytic cells while LTC.sub.4 and LTD.sub.4 were identified as the slow reacting substance of anaphylaxis. It therefore seems reasonable that a potent inhibitor of cyclooxygenase and 5-lipoxygenase, a dual inhibitor, should provide advantages over inhibitiors of cyclooxygenase alone, and many agents of this type are currently under investigation. See Samuelson, B. Science 1983, 220, 568; Venuti, M. C.; Annual Reports in Medicinal Chemistry 1987, 22, 205 and references cited therein. ##STR2##
Recently, 2,6-di-tert-butyl-4-(2-thienoyl) phenol, compound A, was demonstrated to be a novel antiinflammatory agent in several animal models of inflammation. See Moore, G. G. I.; Swingle, K. F. Agents and Actions 1982, 12, 5. Interestingly, A inhibited both the prostaglandin and leukotriene pathways of the arachidonic acid cascade in vitro, although not to an equal extent. In particular, A had an IC.sub.50 of 0.5 mM against cyclooxygenase in a bovine seminal vesicle microsomal enzyme preparation but was fortyfold less potent at inhibiting guinea pig lung 5-lipoxygenase with an IC.sub.50 of 20 mM.
E. S. Lazer et. al., describes analogs of A wherein the thienoyl moeity is replaced by certain 4-arylethenyl groups. See J. Med. Chem. (1989), 32, 100-104. 4-lactonylexomethenyl and 4-(N-methoxypyrrolidinoyl) substituents have also been described. See Ann. Rept. Med. Chem. (1987) Vol 22, 205; Ann. Rept. Med. Chem. (1988) Vol. 23, p. 184. These references, however, do not disclose the novel compounds of the present invention nor do they disclose the relatively equal potency of such compounds against both cyclooxygenase and lipoxygenase.
A 4-benzofuranol, Compound B, has been reported to be a potent and selective inhibitor of LTB.sub.4 biosynthesis in intact rat PMN (IC.sub.50 =0.24 mM). See Belanger, P.; Maycock, A.; Guindon, T.; Bach, T.; Dollob, A. L.; Dufrense, C.; Ford-Hutchinson, A. W.; Gale, P. H.; Hopple, S.; Lau, C. K.; Letts, L. G.; Luell, S.; McFarlane, C. S.; Macintyre, E.; Meurer, R.; Miller, D. K.; Piechuta, H.; Riendeau, D.; Rokach, J.; Rouzer, C.; Scheigetz, J. Canandian Journal of Physiology and Pharmacology 1987, 65, 2441. The selectivity of L-656,224 was shown through its relative lack of activity on cyclooxygenase being a hundred times less potent in the RSV CO assay (IC.sub.50 =25 mM).